Leukocytes (LE) are major contributors to the pathogenesis and progression of many clinical inflammatory disorders, including the systemic inflammatory response syndrome, sepsis and acute respiratory distress syndrome. The need for new and innovative therapies to treat these inflammatory disease states presents a large commercial market opportunity. A large number of therapeutic approaches are under investigation to limit the activation and tissue accumulation of LE at sites of inflammation in order to minimize tissue destruction and disease progression. A therapeutic device within an extracorporeal blood circuit, called the selective cytopheretic device (SCD), sequesters activated LE in a low calcium environment and inhibits their release of inflammatory proteins and cytokines. This Phase II research proposal builds on the Phase I goals which successfully demonstrated the 1st generation SCD1G to have greater therapeutic efficacy with increasing surface area (SA) in a large animal model of septic shock, when compared to sham treated controls, in addition to establishing a simplified SCD extracorporeal circuit for ease of use under standard-of- care hospital settings. This Phase II proposal will determine the design and fabrication of a 2nd Generation SCD2G. Custom SCD2G designs will maintain the low shear force and low ionized calcium environment, shown to be efficacious for SCDG1, with variations to include flow path, flow rates, packing density, and SA, in addition to reduced blood fill volumes which were not achievable with the SCD1G commercially available hollow fiber cartridges. The lower blood fill volume and blood flow rate requirements, will allow SCD2G therapy to be administered via a peripherally inserted central catheter (PICC line) or to criticall ill patients with hemodynamic instability. SCD2G designs will be evaluated in silico via computational flow dynamics simulation to assess casing design and internal device geometry. Prototypes will be fabricated and flow visualization studies performed to determine designs with advantageous flow profiles (Aim 1). In vitro blood circuits with fresh blood will be used to evaluate SCD2G designs selected from in silico studies with respect to hemocompatibility and LE binding characteristics (Aim 2). Lastly, selected SCD2G designs will be evaluated in the porcine model of septic shock used in the Phase I studies. Various renal and cardiovascular parameters, pulmonary inflammation, cytokine levels, systemic neutrophil activation load and time to death will be compared between SCDG2 designs of varying SA and the SCDG1 (Aim 3). SCDG1 therapy has demonstrated an excellent safety profile and compelling efficacy impact in three exploratory clinical trials, reducing mortality rates from the control rate of 60% to 30%, in ICU patients with acute renal failure requiring continuous renal replacement therapy; 50-60% of these patients were also septic. This proposal will determine a finalized SCD2G design to treat a broad array of patients with sepsis, severe sepsis and septic shock and will provide data for an application to the FDA for IDE approval for the SCD to be used in the treatment of sepsis.